Glucagon-like peptide 1 (GLP-1) and the related peptide glucagon are produced via differential processing of proglucagon and have opposing biological activities.
Proglucagon itself is produced in α-cells of the pancreas and in the enteroendocrine L-cells, which are located primarily in the distal small intestine and colon. In the pancreas, glucagon is selectively cleaved from proglucagon. In the intestine, in contrast, proglucagon is processed to form GLP-1 and glucagon-like peptide 2 (GLP-2), which correspond to amino acid residues 78-107 and 126-158 of proglucagon, respectively (see, e.g., Irwin and Wong, 1995, Mol. Endocrinol. 9:267-277 and Bell et al., 1983, Nature 304:368-371). By convention, the numbering of the amino acids of GLP-1 is based on the GLP-1 (1-37) formed from cleavage of proglucagon. The biologically active forms are generated from further processing of this peptide, which yields GLP-1 (7-37)-OH and GLP-1 (7-36)-NH2. The first amino acid of these processed peptides is His7. Both GLP-1 (7-37)-OH (or simply GLP-1 (7-37)) and GLP-1 (7-36)-NH2 have the same activities. For convenience, the term “GLP-1”, is used to refer to both of these forms.
Glucagon is secreted from the α-cells of the pancreas in response to low blood glucose, with the main target organ for glucagon being the liver. Glucagon stimulates glycogen breakdown and inhibits glycogen biosynthesis. It also inhibits fatty acid synthesis, but enhances gluconeogenesis. The net result of these actions is to significantly increase the release of glucose from the liver. GLP-1, in contrast, lowers glucagon secretion, while stimulating insulin secretion, glucose uptake and cyclic-AMP (cAMP) formation in response to absorption of nutrients by the gut. Various clinical data provide evidence of these activities. The administration of GLP-1, for example, in poorly controlled type 2 diabetics normalized their fasting blood glucose levels (see, e.g., Gutniak, et al., 1992, New Eng. J. Med. 326:1316-1322).
GLP-1 has a number of other important activities. For instance, GLP-1 also inhibits gastric motility and gastric secretion (see, e.g., Tolessa, 1998, J. Clin. Invest. 102:764-774). This effect, sometimes referred to as the ileal brake effect, results in a lag phase in the availability of nutrients, thus significantly reducing the need for rapid insulin response.
Studies also indicate that GLP-1 can promote cell differentiation and replication, which in turn aids in the preservation of pancreatic islet cells and an increase in β-cell mass (See, e.g., Andreasen et al., 1994, Digestion 55:221-228; Wang, et al., 1997, J. Clin. Invest. 99:2883-2889; Mojsov, 1992, Int. J. Pep. Prot. Res. 40:333-343; and Xu et al., 1999, Diabetes 48:2270-2276). Evidence also indicates that GLP-1 can increase satiety and decrease food intake (see, e.g., Toft-Nielsen et al., 1999, Diabetes Care 22:1137-1143; Flint et al., 1998, J. Clin. Invest. 101:515-520; Gutswiller et al., 1999 Gut 44:81-86).
Other research indicates that GLP-1 induces β-cell-specific gene expression, including GLUT-1 transporter, insulin receptor and hexokinase-1 (see, e.g., Perfetti and Merkel, 2000, Eur. J. Endocrinol. 143:717-725). Such induction could reverse glucose intolerance often associated with aging.
Because GLP-1 plays a key role in regulating metabolic homeostasis, it is an attractive target for treating a variety of metabolic disorders, including diabetes, obesity and metabolic syndrome. Current treatments for diabetes include insulin injection and administration of sulfonylureas, metformin and TZDs. These approaches, however, have significant shortcomings. Insulin injections, for instance, require complicated dosing considerations, and treatment with sulfonylureas often becomes ineffective over time, metformin can induce hypoglycemia and TZDs have side effects such as body weight gain and edema. Potential advantages of GLP-1 therapy include: 1) increased safety because insulin secretion is dependent on hyperglycemia, 2) suppression of glucagon secretion which in turn suppresses excessive glucose output, and 3) slowing of gastric emptying, which in turn slows nutrient absorption and prevents sudden glucose increases.
A key hurdle for effective treatment with GLP-1, however, has been the very short half-life of the peptide, which typically is only a few minutes (see, e.g., Holst, 1994, Gastroenterology 107:1848-1855). Various analogs have been developed with the goal of extending the half-life of the molecule. Some of these, however, have significant gastrointestinal side effects, including vomiting and nausea (see, e.g., Agerso et al., 2002, Diabetologia 45:195-202).
Accordingly, there thus remains a need for improved molecules that have GLP-1 type activity, for use in the treatment of various metabolic diseases such as diabetes, obesity, irritable bowel syndrome and metabolic syndrome.